This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Infections caused by multidrug-resistant bacteria have become a global public health crisis. In particular, infections due to multidrug-resistant staphylococci have been increasing at an alarming rate. Clinically, Staphylococcus aureus was once susceptible to most antibiotics. However, the emergence of antibiotic-resistance in S. aureus has occurred in a series of waves. Starting in the mid-1940s, isolates of S. aureus were discovered that produced a plasmid-encoded penicillinase capable of hydrolyzing the β-lactam ring of penicillin thus rendering the antibiotic ineffective. Penicillin-resistant strains shortly began to cause community infections, and by the early 1950s they had become pandemic (P M Rountree, et al., Med. J. Aust. 1955, 42, 157-161). The first reports of a S. aureus strain that was resistant to methicillin (MRSA) were published in 1961 (M P Jevons, Br. Med. J. 1961, 1, 124-125). Outbreaks of infections caused by different MRSA strains were reported in hospitals in the United States in the late 1970s; by the 1980s these strains were endemic, leading to the worldwide pandemic of MRSA in hospitals that continues today. Although global in its distribution and impact, MRSA was still confined mostly to health care facilities. In 2013, the Centers for Disease Control and Prevention (CDC) reported more than 11,000 people died from a MRSA-related infection in the United States of America alone (M A Fischbach, et al., Science 2009, 325, 1089-1093). Egypt is among several Mediterranean countries that are experiencing a surge in MRSA infections. The prevalence of MRSA in both Egyptian community and hospital-acquired pyogenic skin and soft tissue infections is currently alarming.
Over the last 40 years, the ever-increasing burden of MRSA infections led to the increased use of vancomycin, an agent of last resort for treatment of recalcitrant MRSA infections. This intensive selective pressure resulted in the emergence of vancomycin-intermediate S. aureus (VISA), and vancomcyin-resistant S. aureus (VRSA) isolates (L M Weigel, et al, Science 2003, 302, 1569-1571). Compounding the problem further, the effectiveness of vancomycin is limited by prolonged, persistent or recurrent bacteremia during therapy, high rates of microbiological and clinical failures, nephrotoxicity and the increasing prevalence of non-susceptible strains (J C Dombrowski, et al, J. Infect. 2008, 57, 110-115).
In addition to exhibiting resistance to vancomycin, MRSA isolates resistant to a wide variety of antibacterial classes including the β-lactam antibiotics, macrolides and fluoroquinolones have been found (H F Chambers, N. Engl. J. Med. 2005, 352, 1485-1487; G J Moran, et al., N. Engl. J. Med. 2006, 355, 666-674). Collectively this points to the pressing need to develop novel antimicrobial agents.